Variant rs760351849 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM4PP5BS2_Supporting

The NM_001374675.1(HSF4):c.426_443dupGGTGCAGGCTTTGCGGGG(p.Gly148_Val149insValGlnAlaLeuArgGly) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,474,414 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000076 ( 1 hom. )

Consequence

HSF4
NM_001374675.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 0.507

Variant links:

Genes affected

HSF4 (HGNC:5227): (heat shock transcription factor 4) Heat-shock transcription factors (HSFs) activate heat-shock response genes under conditions of heat or other stresses. HSF4 lacks the carboxyl-terminal hydrophobic repeat which is shared among all vertebrate HSFs and has been suggested to be involved in the negative regulation of DNA binding activity. Two alternatively spliced transcripts encoding distinct isoforms and possessing different transcriptional activity have been described. [provided by RefSeq, Jul 2008]

HSF4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001374675.1.

PP5

Variant 16-67166010-A-AGGTGCAGGCTTTGCGGGG is Pathogenic according to our data. Variant chr16-67166010-A-AGGTGCAGGCTTTGCGGGG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522680.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

BS2

High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSF4	NM_001374675.1 link	c.426_443dupGGTGCAGGCTTTGCGGGG	p.Gly148_Val149insValGlnAlaLeuArgGly	disruptive_inframe_insertion	4/13	ENST00000521374.6	NP_001361604.1
HSF4	NM_001040667.3 link	c.426_443dupGGTGCAGGCTTTGCGGGG	p.Gly148_Val149insValGlnAlaLeuArgGly	disruptive_inframe_insertion	6/15		NP_001035757.1	Q9ULV5-1A0A024R6X7
HSF4	NM_001374674.1 link	c.426_443dupGGTGCAGGCTTTGCGGGG	p.Gly148_Val149insValGlnAlaLeuArgGly	disruptive_inframe_insertion	4/13		NP_001361603.1
HSF4	NM_001538.4 link	c.426_443dupGGTGCAGGCTTTGCGGGG	p.Gly148_Val149insValGlnAlaLeuArgGly	disruptive_inframe_insertion	6/15		NP_001529.2	Q9ULV5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSF4	ENST00000521374.6 link	c.426_443dupGGTGCAGGCTTTGCGGGG	p.Gly148_Val149insValGlnAlaLeuArgGly	disruptive_inframe_insertion	4/13	1	NM_001374675.1	ENSP00000430947.2		Q9ULV5-1

Frequencies

GnomAD3 genomes

AF:

0.0000351

AC:

AN:

142618

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000528

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000453

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000758

AC:

101

AN:

1331796

Hom.:

Cov.:

AF XY:

0.0000898

AC XY:

AN XY:

656806

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000757

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000899

Gnomad4 OTH exome

AF:

0.0000185

GnomAD4 genome

AF:

0.0000351

AC:

AN:

142618

Hom.:

Cov.:

AF XY:

0.0000435

AC XY:

AN XY:

68992

show subpopulations

Gnomad4 AFR

AF:

0.0000528

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000453

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2024

In-frame insertion of 6 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge -

Cataract 5 multiple types

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 03, 2017

- -

HSF4-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 13, 2022

The HSF4 c.426_443dup18 variant is predicted to result in an in-frame duplication (p.Ala145_Gln150dup). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-67199913-A-AGGTGCAGGCTTTGCGGGG). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over